An Efficacy and Safety Study Of Pracinostat In Combination With Azacitidine In Adults With Acute Myeloid Leukemia

Acute Myeloid Leukemia Clinical Trial

Official title:

A Phase III, Double-Blind, Placebo-Controlled, Multicenter, Randomized Study Of Pracinostat In Combination With Azacitidine In Patients ≥18 Years With Newly Diagnosed Acute Myeloid Leukemia Unfit For Standard Induction Chemotherapy

Clinical Trial Details — Status: Terminated

Administrative data

• NCT number: NCT03151408
• Other study ID #: PRAN-16-52
• Status: Terminated
• Phase: Phase 3
• Start date: June 23, 2017
• Est. completion date: August 20, 2020

Study information

• Verified date: February 2022
• Source: Helsinn Healthcare SA
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

This is a Phase III, multicenter, double-blind, randomized study of pracinostat vs. placebo with azacitidine (AZA) as background therapy in patients ≥ 18 years of age with newly diagnosed acute myeloid leukemia (AML), excluding acute promyelocytic leukemia and cytogenetic low-risk AML, who are unfit to receive intensive remission induction chemotherapy due to age ≥ 75 years or comorbidities. Patients will be randomized in a 1:1 ratio to one of two groups: Group A (experimental group) to receive pracinostat plus AZA and Group B (control group) to receive placebo plus AZA. Randomization will be stratified by cytogenetic risk category (intermediate vs. unfavorable-risk, according to SWOG Cytogenetic Risk Category Definitions) and ECOG performance status (0-1 vs. 2). Treatments will be administered based on 28-day cycles, with pracinostat/placebo administered orally once every other day, 3 times a week for 3 weeks, followed by one week of no treatment and AZA administered for 7 days of each cycle. Study treatment should continue until there is documented disease progression, relapse from complete remission (CR), or non-manageable toxicity. A minimum of 6 cycles may be required to achieve a complete remission. Once permanently discontinued from study treatment, patients will enter the Long-term Follow-up phase of the study and will be followed for assessment of disease progression, if applicable, and survival every 3 months (±1 month) until death. The end of this study is defined when 390 events (deaths) have occurred and the study is unblinded for final overall survival analysis. Patients who are receiving study treatment at the end of the study may have the opportunity to continue to receive the study drugs to which they were randomized to (Post- Study Observation Period), until the Sponsor informs the Investigators of the appropriate course of action based on the study results. The Post-Study Observation Period is defined as the period starting from the end of the study for a maximum of 12 months.

Recruitment information / eligibility

• Status: Terminated
• Enrollment: 406
• Est. completion date: August 20, 2020
• Est. primary completion date: August 20, 2020
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

1. Male or female patient = 18 years of age with newly diagnosed, histologically or cytologically confirmed, AML including de novo, secondary to antecedent hematologic disorders, or treatment-related disease with intermediate or unfavorable-risk cytogenetics

2. Unable to receive intensive chemotherapy regimens at enrollment, based on one of the following: I. Age = 75 years, or

II. Age < 75 years with at least 1 of the following co-morbidities:

1. An ECOG performance status of 2

2. Clinically significant cardiovascular disease defined as:

i. Left ventricular ejection fraction (LVEF) = 50%, measured within 3 months prior to Day 1 confirmed by ECHO/MUGA ii. Congestive heart failure requiring medical therapy iii. Chronic stable angina requiring medical therapy iv. Prior cerebrovascular accident with sequelae c. Clinically significant pulmonary disease defined as: i. Forced expiratory volume in 1 second (FEV1) = 65% of expected ii. Lung diffusing capacity for carbon monoxide (DLCO) = 65% of expected Confirmed by pulmonary tests. d. Diabetes mellitus with symptomatic end-organ damage (e.g., retinopathy, nephropathy, neuropathy, vasculopathy) e. Autoimmune inflammatory conditions (e.g., rheumatoid arthritis, systemic lupus erythematous, inflammatory bowel disease, or similar) requiring chronic disease modifying therapy (e.g., etanercept, adalimumab, infliximab, rituximab, methotrexate, or similar) f. Class III obesity defined as a Body Mass Index (BMI) > 40 kg/m2 g. Renal impairment defined as serum creatinine > 1.3 mg/dL (> 115 µmol/L) or creatinine clearance <70 ml/min h. Clinically significant cognitive impairment defined as requiring medical therapy and/or assistance with activities of daily living

3. 20% blasts in bone marrow

4. Peripheral white blood cell (WBC) count 30,000/µL For cyto-reduction, hydroxyurea is allowed during screening and up to Cycle 1, Days 1-14, to reduce WBC count to < 30,000 µL prior to Day 1. After Cycle 1, Day 14, hydroxyurea is prohibited.

5. ECOG performance status = 2

6. Adequate organ function as evidenced by the following laboratory findings:

1. Total bilirubin = 2 × upper limit of normal (ULN) or < 3 x ULN for patients with Gilbert-Meulengracht Syndrome

2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) = 2.5 × ULN

7. Serum creatinine = 1.5 × ULN according to institutional standards or creatinine clearance = 50 mL/min

8. QT-interval corrected according to Fridericia's formula (QTcF) = 450 ms on electrocardiogram (ECG) at Screening

9. Male patient who is surgically sterile, or male patient who is willing to agree to remain completely abstinent (refrain from heterosexual intercourse) or who use barrier contraceptive measures and agree to refrain from donating sperm during the entire study treatment period and for 3 months after the last administration of study drug

10. Female patient who is of childbearing potential willing to use adequate contraceptive measures while participating on study, OR willing to completely abstain from heterosexual intercourse during the entire study treatment period

11. Female patient who is of childbearing potential must have a negative serum pregnancy test result within 3 weeks prior to starting study drugs.

12. Willing to provide voluntary written informed consent before performance of any study related procedure not part of normal medical care

13. Willing and able to understand the nature of this study and to comply with the study and follow-up procedures.

Exclusion Criteria:

1. Able to receive intensive induction chemotherapy

2. AML-associated inv(16)/t(16;16)/del(16q), t(15;17) (i.e. promyelocytic leukemia) with/without secondary aberrations; t(8;21) lacking del (9q) or complex karyotypes

3. Presence of an active malignant disease within the last 12 months, with the exception of adequately treated cervical cancer in-situ, non-melanoma skin cancer and superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ] and T1 [tumor invades lamina propria]). Other malignancies may be considered after consultation with the Medical Monitor

4. Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction that, in the Investigator's opinion, could compromise the patient's safety or put the study outcomes at risk

5. Uncontrolled arrhythmias; any Class 3-4 cardiac diseases as defined by the New York Heart Association (NYHA) functional classification

6. Evidence of AML central nervous system (CNS) involvement

7. Previous chemotherapy for AML except for the following, which are allowed:

1. Hydroxyurea for cytoreduction

2. One course of hypomethylating agent therapy (i.e.; up to 7 doses of azacitidine or 3-5 days of decitabine) within 30 days prior to enrollment (Day 1)

8. Use of experimental drugs = 30 days prior to screening

9. Received prior HDAC inhibitor therapy

10. Received prior treatment with a hypomethylating agent, except as allowed in Exclusion Criterion 7.b

11. Known hypersensitivity to any components of pracinostat, azacitidine, or mannitol

12. History of human immunodeficiency virus (HIV) or an active and uncontrolled infection with hepatitis C virus (HCV) or hepatitis B virus (HBV)

13. Gastrointestinal (GI) tract disease that causes an inability to take oral medication, malabsorption syndrome, or a requirement for IV alimentation; prior surgical procedures affecting absorption; or uncontrolled inflammatory GI disease (e.g., Crohn's disease, ulcerative colitis)

14. Any disease(s), psychiatric condition, metabolic dysfunction, or findings from a physical examination or clinical laboratory test result that would cause reasonable suspicion of a disease or condition, that contraindicates the use of pracinostat and/or AZA, that may increase the risk associated with study participation, that may affect the interpretation of the results, or that would make the patient inappropriate for this study

15. Breast-feeding woman

16. current smokers(use of patches, chewing gums and vaping nicotine conaining fluids is permitted). Patients who stopped smoking at least 8 day prior to first pracinostat dosing can be enrolled, provided they refrain from smoking during the whole study

17. prohibited concomitant medications

18. uncontrolled infections

19. receive more than 1 prior cycle of HMA or bone marrow transplant for any prior hematological disorder antecedent to AML

Related Conditions & MeSH terms

• Acute Myeloid Leukemia
• Leukemia
• Leukemia, Myeloid
• Leukemia, Myeloid, Acute

Intervention

Drug:
• Pracinostat
60 mg capsule
• Placebos
capsule
• Azacitidine
SC or IV injection

Locations

Country	Name	City	State
Argentina	Hospital italiano de Buenos Aires	Ciudad Autonoma de Buenos Aire	Buenos Aires
Argentina	Instituto Medico Especializado Alexander Fleming	Ciudad Autonoma de Buenos Aire	Buenos Aires
Argentina	H ospi tal Privado de Cordoba	Córdoba
Argentina	sanatorio Allende	Córdoba
Argentina	hospital Italiano la Plata	La Plata	Buenos Aires
Argentina	Sanatorio Britanico SA Paraguay 40, 3P	Rosario	Santa Fe
Australia	Sunshine coast university hospital	Birtinya	Queensland
Australia	The Northern hospital Pharmacy Department, Ground Floor	Epping	Victoria
Australia	Barwon Health, University Hospital Geelong	Geelong	Victoria
Australia	Austin Hospital, Clinical Trial Pharmacy	Heidelberg	Victoria
Australia	Royal Hobart Hospital	Hobart	Tasmania
Australia	Liverpool hospital	Liverpool
Australia	Liverpool Hospital	Liverpool	New South Wales
Australia	Royal Perth Hospital	Perth
Australia	Prince of Wales Hospital	Randwick
Austria	Krankenhaus der Elisabethinen Linz GmbH	Linz
Austria	Müllner Hauptstrabe 48	Salzburg
Austria	General Hospital Hietzing	Vienna
Brazil	Hospital de Cancer de Barretos	Barretos
Brazil	Hospital Santa Casa de Belo Horizonte -Serviyo de Oncologia Clinica	Belo Horizonte
Brazil	Liga Paranaense de Com bate ao Cancer - Hospital Erasto Gaertner	Curitiba	Paranà
Brazil	Centro de Pesquisas Oncologicas - CEPON	Florianópolis
Brazil	Ce ntro de Pesquisas Hospital Amara l Ca rvalh o	Jau	SP
Brazil	Hospital de ClÃ-nicas de Porto Alegre	Porto Alegre
Brazil	Institute Nacional de Cancer Jose de Alencar Gomes da Silva-INCA	Rio De Janeiro
Brazil	Faculdade de Medicina do ABC - Centro de Estudos e Pesquisas de Hematologia e Oncologia	Santo André
Brazil	Hospital de Base de Sao Jose do Rio Preto	São José Do Rio Preto
Brazil	Centro de Pesquisa Clinica do Hospital Santa Marcelina	São Paulo	SP
Czechia	"Fakultni nemocnice Hradec Kralove,	Hradec Králové
Czechia	Fakultni nemocnice Olomuc	Olomouc
Czechia	"Fakultni nemocnice Kralovske Vinohrady,	Praha
Czechia	Fakultni nemocnice Kralovske Vinohrady,	Praha
Czechia	Vseobecna fakultni nemocnice	Praha 2
France	CHU Amiens Picardie-Site Sud-Service d'Hematologie	Amiens
France	L'Hopital privé du Confluent SAS	Nantes
France	CHU de Nice, Archet 1 Hospital-Hematology department	Nice
France	Hospital saints Louis	Paris
France	Haut-Leveque-Service d'hématologie clinique et de thérapie cellular	Pessac
France	Centre Hospitalier Lyon Sud	Pierre-Bénite
France	Centre Henri Becquerel	Rouen Cedex 1
Germany	Klinikum St. Marien Amberg	Amberg	Bayern
Germany	Charité-Universitätsmedizin - 1. Campus Mitte	Berlin
Germany	Klinikum Chemnitz gGmbH	Chemnitz
Germany	Universitatsklinikum Erlangen	Erlangen	Bavaria
Germany	SRH Wald-Klinikum Gera GmbH	Gera
Germany	Marien Hospital Herne-Universitätsklinikum der Ruhr-Universität Bochum	Herne	North Rhine-westphalia
Germany	Staedtisches krankenhaus kiel	Kiel
Germany	Universitaet Mainz	Mainz
Hungary	St. Istvan & St. Laszlo Hospital, Deapartment of Hematology and Stem Cell Transplantation	Budapest
Hungary	University of Debrecen Clinical Center	Debrecen
Hungary	Somogy Megyei Kaposi Mor Oktato Korhaz, Dep. Of Haematology	Kaposvár
Hungary	Szabolcs-Szatmar-Bereg megyei Korhazak es Egyetemi Oktatokorhaz â€" Josa Andras Oktatokorhaz, Hematologiai Osztaly	Nyiregyhaza
Hungary	Pecsi Egyetem I. Belgy6gyaszati Klinika	Pécs	Baranya
Hungary	university of Pécs	Pécs	Baranya
Italy	AOU Policlinico Consorziale di Bari	Bari
Italy	AOU Policlinico Sant'Orsola-Malpighi	Bologna
Italy	Azienda Ospedaliera-Università Careggi	Firenze
Italy	Ospedale Policlinico San Martino	Genova
Italy	ospedale Vito Fazzi	Lecce
Italy	Ospedale San Raffaele-U.O. Ematologia e TMO	Milano	Lombardia
Italy	Azienda Ospedaliere Antonio Cardarelli,	Naples
Italy	Azienda Ospedaliera Universitaria Federico II	Napoli
Italy	Ospedale la Maddalena, UO Oncoematologia e TMO	Palermo	PA
Italy	Fondazione IRCCS policlinico San Matteo Pavia	Pavia
Italy	Fondazione PTV-Policlinico Tor Vergata	Roma
Italy	Policlinico Universitario Gemelli	Roma
Italy	Azienda Ospedaliera Ordine Mauriziano	Torino
Korea, Republic of	Inje university Busan Paik Hospital	Busan
Korea, Republic of	Chonnam National University Hwasun Hospital	Hwasun
Korea, Republic of	Gachon University Gil medical center, div hematology	Incheon
Korea, Republic of	Seoul National University Hospital, Div.Hematology/Oncology	Seoul
Korea, Republic of	Seoul St.Mary Hospital, div hemato-oncology	Seoul
Korea, Republic of	Sumsung medical center	Seoul
Korea, Republic of	Ulsan University Hospital	Ulsan
Poland	Wojewodzkie Wielospecjalistyczne Centrum onkologii I traumatologii	Lódz
Poland	Examen Sp. Z o.o.,	Poznan
Poland	Specjalistyc:my Szpi tal im. dra Alfreda Sokolowskiego	Walbrzych
Poland	Uniwersytecki Szpital Kliniczny	Wroclaw
Romania	clinical hospital Coltea Bld	Bucuresti
Romania	Spitalul Clinic Colentina	Bucuresti
Romania	Spitalul Universitar de Urgenta Bucuresti	Bucuresti
Romania	Oncological Institute "Ion Chiricuta"	Cluj-Napoca
Romania	Spitalul Clinic Filantropia	Craiova	Jud.dolj
Romania	institutu Regional de Oncologie Iasi	Iasi
Spain	Hosp.Universitario A Coruña-Hospital Teresa Herrera	A Coruña	Galicia
Spain	Institut Català D'Oncologia (ICO)	Badalona	Barcelona
Spain	"Hospital Universitario Vall d'Hebron	Barcelona
Spain	Hospital de La Santa Creu i Sant Pau	Barcelona
Spain	Hospital San Pedro de Alcantara	Caceres	Extremadura
Spain	Hospital Clinico San Carlos	Madrid
Spain	Hospital Univers itario HM Sanchinarro	Madrid
Spain	Hospital Universitario la Paz	Madrid
Spain	Hospital Universitario Son Espases	Palma De Mallorca	Isla Baleares
Spain	Hospital Uni vcrsitario de Salamanca	Salamanca
Spain	Hospital Universitario Virgen del Rocio	Sevilla
Spain	Hospital Universitario y Politecnico de La Fe	Valencia
Taiwan	Changhua Christian Hospital	Changhua
Taiwan	Hematology and Oncology, Changhwa Christian Hospital	Changhua
Taiwan	Kaohsiung Chang Gung Memorial Hospital	Kaohsiung
Taiwan	Kaohsiung Medical University Chung-Ho Memorial Hospital	Kaohsiung
Taiwan	China Medical University Hospita	Taichung
Taiwan	Division of Hematology, National Taiwan University Hospital	Taipei
Taiwan	koo-Foundation Sun Yat-Sen Cancer Center	Taipei
United Kingdom	Blackpool Teaching Hospitals NHS Foundation Trust	Blackpool	Lancashire
United Kingdom	Bradford Teaching Hospitals NHS Foundation trust	Bradford
United Kingdom	University Hospitals Coventry and Warwickshire NHS Trust	Coventry
United Kingdom	Royal Devon & Exeter Hospital (Wonford site)	Exeter	Devon
United Kingdom	Royal Liverpool University Hospital	Liverpool
United States	Rcca Md Llc	Bethesda	Maryland
United States	Saint alphonsus Regional medical center-cancer care center	Boise	Idaho
United States	Emily Couric Clinical cancer center	Charlottesville	Virginia
United States	University Hospital Cleveland Medical Center	Cleveland	Ohio
United States	Pontchartrain Cancer Center (Research Location)	Covington	Louisiana
United States	VA North texas Health Care sytem,Dallas VA Medical Center div. Hematology Oncology	Dallas	Texas
United States	Duke University Medical Center-2400 Pratt Street	Durham	North Carolina
United States	Michigan Center of Medical Research	Farmington Hills	Michigan
United States	GHS Cancer Institute	Greenville	South Carolina
United States	MD Anderson Cancer Center	Houston	Texas
United States	100 Mercy Way	Joplin	Montana
United States	University of Tennessee Medical Center	Knoxville	Tennessee
United States	10666 N.Torrey Pines-Scripps Cancer Center	La Jolla	California
United States	UC San Diego Moores Cancer Center	La Jolla	California
United States	Michigan State University	Lansing	Michigan
United States	Norton Cancer Institute, St. Matthews Campus	Louisville	Kentucky
United States	Loyola University Chicago	Maywood	Illinois
United States	Mercy Clinic Oncology & Hematology	Oklahoma City	Oklahoma
United States	Mayo clinic hospital	Phoenix	Arizona
United States	Mayo clinic	Rochester	Minnesota
United States	Swedish Cancer Institute	Seattle	Washington
United States	Thomas Reeve Chauncey	Seattle	Washington
United States	Mercy Research	Springfield	Missouri
United States	Stony Brook University	Stony Brook	New York
United States	Arizona Oncology Associates, East Valley Cancer Center	Tempe	Arizona
United States	University of Arizona cancer center-north campus	Tucson	Arizona
United States	Oklahoma cancer specialist and research institute	Tulsa	Oklahoma
United States	Georgetown University Medical Center	Washington	District of Columbia
United States	Universitz of Kansas Cancer Center	Westwood	Kansas
United States	UMass Memorial medical center-university campus	Worcester	Massachusetts

Sponsors (2)

Lead Sponsor	Collaborator
Helsinn Healthcare SA	Clinipace Worldwide

Countries where clinical trial is conducted

United States,  Argentina,  Australia,  Austria,  Brazil,  Czechia,  France,  Germany,  Hungary,  Italy,  Korea, Republic of,  Poland,  Romania,  Spain,  Taiwan,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Composite Complete Remission (cCR) Rate	Composite complete remission (cCR) rate is the proportion of patients who achieve either a disease response of CR, CRi or MLFS (i.e., cCR = CR + CRi + MLFS) within the study period, according to the response criteria	744 days
Other	Duration of Composite Complete Remission	Duration of cCR response is the time from first cCR until documented relapse (the definition of relapse from CR will be applied) or death. Duration of cCR is only defined for patients who achieve a cCR	744 days
Other	Change in Quality of Life From Baseline (EORTC QLQ-C30 - European Organisation for Research and Treatment of Cancer Quality-of-life Questionnaire Core 30)	QLQ-C30 is made of multi-item scales and single-item measures (functional and symptom scales, a global health status/QoL scale and single items). Item range is the difference between possible max and min response to individual items of the scale; most items take values from 1 to 4 (range=3). Global health status takes values from 1 to 7 (range = 6). For statistical analysis purpose, single-item and scale values were all standardized (according to linear transformation described in Scoring Manual) to obtain scores ranging 0-100. An high scale score represents an higher response level. Thus an high score for a functional scale represents an high/healthy level of functioning, an high score for the global health status/QoL represents a high QoL, an high score for a symptom scale/item represents an high level of symptomatology/problems.	from baseline up to 660 days
Other	Relapse Free Survival	the time from the date of achievement of CR or CRi until the date of relapse or death from any cause	744 days
Other	Progressive Free Survival Rate (PFS)	PFS is defined as the time from the date of randomization until the date of relapse (progression), or death from any cause, whichever occurs first.	800 days
Other	Duration of Morphologic CR	Duration of morphologic CR is defined as the time from the date of achievement of CR until the date of relapse (progression).	744 days
Other	Time to CR	Time to CR is defined as the time from the date of randomization until the date of CR in the absence of interceding therapies. The analysis set was the ITT set.	616 days
Other	Morphologic CR Within 6 Cycles Rate	Morphologic CR within 6 cycles rate is defined as the proportion of patients who achieved CR in the absence of interceding therapies within 6 treatment cycles (i.e., during treatment phase up to Day 1 of Cycle 7 included). Analysis was performed in the ITT set.	within 6 cycles
Primary	Overall Survival	OS measures the time from randomization to death due to any cause.	826 days
Secondary	Morphologic Complete Remission (CR) Rate	The CR rate is the proportion of patients who achieve a morphologic CR according to the response criteria; <5% blasts in a bone marrow aspirate sample with spicules; There should be no blasts with Auer rods; No EMD; Absolute Neutrophil Count (ANC) =1,000/µL; Platelet count of =100,000/µL; Patient must be independent of transfusions (for at least 1week before each assessment)	744 days
Secondary	Complete Remission Without Minimal Residual Disease (CRmrd) Rate	proportion of patients who achieve a CR without minimal residual disease by multicolor flow cytometry according to the following criteria; Morphologic CR; Minimal Residual Disease (MRD) by MFC negative	826 days
Secondary	Cytogenetic Complete Remission (CRc) Rate	The CRc rate is the proportion of patients who achieve a reversion to a normal karyotype at CR within the study period. This endpoint applies only to patients with abnormal cytogenetic at enrollment according to the following criterion; Morphologic CR plus reversion to a normal karyotype (defined as no clonal abnormalities detected in a minimum of 20 mitotic cells)	826 days
Secondary	Transfusion Independence (TI)	Transfusion independence rate is defined as the proportion of patients who show eight weeks or over without red blood cell (RBC-TI) and/or platelet (PLT-TI) transfusion during study period	826 days